PROJECT SUMMARY Napping is highly prevalent in the elderly, particularly in patients with Alzheimer's disease, but the longitudinal effects of napping on neurodegeneration are poorly understood. While growing evidence suggests that sleep disturbances lead to increased risk of Alzheimer's disease, it is unclear whether napping, as a crucial part of the 24-h sleep-wake cycle, could be as important a risk factor as nocturnal sleep for Alzheimer's disease. This Pathway to Independence Award (K99/R00) application by Dr. Yue Leng intends to fill this knowledge gap by building on her prior epidemiologic research that suggests associations between self-reported napping and risk of various adverse health outcomes in the elderly, and will provide Dr. Leng with further focused trainings to facilitate her transition into an independent researcher in the field of napping, sleep and cognitive aging. The research aims during the K99 phase are to determine the independent and longitudinal effects of actigraphy- measured napping on cognitive decline and risk of incident mild cognitive impairment (MCI) and Alzheimer's disease, and to explore and elucidate potential mechanisms, including inflammation, oxidative stress, metabolic dysregulation and other comorbidities. Different dimensions of napping (i.e., intention, duration, frequency and timing) will also be explored and used to inform the development of a treatment program in R phase. This project will leverage data from two NIA-funded state-of-the-art prospective studies of aging, the Osteoporotic Fractures in Men (MrOS) Study andStudy of Osteoporotic Fractures (SOF), both with 24-hour actigraphy recordings of napping and nocturnal sleep, widely used cognitive tests and serum biochemical measures. These research activities will be complemented by focused trainings in 1) etiology, diagnosis and management of Alzheimer's and other dementias; 2) interventional study design and conduct; and 3) aging- related sleep medicine. The training goals will be supervised by a multidisciplinary mentorship team, led by Dr. Kristine Yaffe, MD, Professor of Psychiatry, Neurology and Epidemiology. By the end of the training phase, Dr. Leng will develop expertise in sleep measurement and intervention to successfully transition into the R00 project, which aims to develop and pilot test a treatment program that incorporates bright light therapy and a modified cognitive behavioral therapy for insomnia (CBT-i) to improve 24-hour patterns of sleep in patients with MCI or mild Alzheimer's disease, with the ultimate aim of decreasing risk of Alzheimer's onset or progression. The combined 5-year research and training plan will allow Dr. Leng to establish an independent research program dedicated to the improvement of both sleep and aging outcomes. The current proposal will also specifically 1) advance knowledge about the effects of napping, an extremely common but understudied behavior in the elderly, on cognitive aging; 2) develop a novel sleep treatment program targeting patients with MCI; and 3) pilot a line of research on interventions of 24-h sleep patterns in order to improve cognitive outcomes and prevent Alzheimer's disease in high-risk population.